YC-001
目录号 : GC64384
YC-001 是一种非视黄醛化合物，经证实对视杆细胞视蛋白 具有反向激动剂和拮抗剂活性。
Cas No.:748778-73-6
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >99.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
| Cell experiment [1]: | |
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Cell lines |
Transfected 27 adRP-causing hRHO mutants to NIH3T3 cells |
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Preparation Method |
NIH3T3 cells were seeded at 5000 cells/well and cultured in a blackwall, clear bottom, and poly-L-lysine-treated 384-well plate at 37 °C with 5% CO2 on day 1, and then transfected with the plasmids containing hRHO cDNA mutants on day 2. On day 3, cells were treated with 0.1% DMSO, 5 µM 9-cis-retinal (under dim red light), 40 µM YC-001, or 20 µM F5257-0462 in DMEM with 10% FBS for 24 h. On day 4, treated cells were fixed with 4% paraformaldehyde (PFA) in the dark for 20 min and immunostained with 15µL/well of 20 µg/mL Alexa488-conjugated B6-30 anti-RHO antibody and Hoechst 33342 (1:10,000 dilution). |
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Reaction Conditions |
40 µM for 24 h |
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Applications |
YC-001 rescued multiple of 27 adRP-causing RHO mutants to NIH3T3 cells. 9-cis-retinal, F5257-0462, and YC-001 rescued cell surface transport of 16, 11, and 7 mutants, respectively. |
| Cell experiment [1]: | |
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Explant |
Retinal explants |
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Preparation Method |
Mice were euthanized at P15, and eyes were enucleated and incubated in Ames’ solution containing L-cysteine (0.22 mM) and papain (20 U/mL) at 37°C for 30 minutes, followed by incubation in DMEM with 10% FBS at 4°C for 5 minutes. Each eye cup was made and flattened by 4 cuts, and sclera was removed leaving only RPE attached to retina. Each retinal explant (RPE layer facing down) was cultured in a transwell in a 6-well plate with neurobasal plus medium containing 2% B27 supplement and 5 μg/mL of plasmocin at 37°C with 5% CO2 for 24 hours. The retinal explants were then treated with the same medium containing 40 μM YC-001 or DMSO. Fresh medium with the compound was changed daily. |
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Reaction Conditions |
40 μM YC-001 for 48 h |
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Applications |
YC-001 increases the percentage of ciliary targeted RHOP23H primarily by decreasing the level of misfolded RhoP23H mutant in the the outer nuclear layer, which is contributed by reduced total RHOP23H protein load. |
| Animal experiment [2]: | |
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Animal models |
Abca4−/−Rdh8−/− mice with a 129 Sv/Ev or C57BL/6 mixed background |
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Preparation Method |
Retinal degeneration was initiated by exposing Abca4−/−Rdh8−/− mice for 30 min to white light with an intensity of 10,000 lux. Pupils of mice were dilated with 1% tropicamide 3 min before bright light exposure. YC-001 or DMSO were administered i.p. 30 min before such exposure. The effects of YC-001 were tested at two dosages: 50 and 200 mg kg−1 bw. The volume of each injection was less than 50 µL. |
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Dosage form |
4 μg/μl, 2 μl, lateral cerebral ventricle injection |
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Applications |
DMSO-treated mouse retinas featured significantly diminished outer nuclear layers (ONLs), indicating the loss of photoreceptor cells, YC-001-treated mice evidenced a dose-dependent protection of the ONL from light-induced damage. |
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References: [1]. Vats A, Xi Y, Feng B, et al. Nonretinoid chaperones improve rhodopsin homeostasis in a mouse model of retinitis pigmentosa[J]. JCI insight, 2022, 7(10). [2]. Chen Y, Chen Y, Jastrzebska B, et al. A novel small molecule chaperone of rod opsin and its potential therapy for retinal degeneration[J]. Nature communications, 2018, 9(1): 1-18. |
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YC-001 is a non-retinal compound that has been revealed to have both inverse agonist and antagonist activity toward rod opsin [1]. Cell-based β-Gal fragment complementation activity of YC-001 (EC50: 8.7μM) showed a potency of 7.8 μM and an efficacy at 150-310% of the control activity score [1].
YC-001 (0.5, 1, 5, 10, 20, 40 μM) improves the glycosylation profile of P23H opsin mutant [1]. YC-001 (0,-1.5 μM) reversibly binds rod opsin with EC50 of 0.98 μM [1]. YC-001 (0.313, 0.625, 1.25, 2.5, 5, 10, 20, 80 μM) increases in cAMP level in a dose-dependent manner in NIH3T3 cells [1]. YC-001 rescued multiple of 27 adRP-causing RHO mutants to NIH3T3 cells. 9-cis-retinal, F5257-0462, and YC-001 rescued cell surface transport of 16, 11, and 7 mutants, respectively [2].
YC-001(40 μM, 48 h) increases the percentage of ciliary targeted RHOP23H primarily by decreasing the level of misfolded RhoP23H mutant in the ONL, which is contributed by reduced total RHOP23H protein load [2]. YC-001 improves RHO protein quality and proteostasis of the RhoP23H/+ retinae [2].YC-001 showed a TC50 (the toxic concentration of a chemical that causes the cells growing 50% as well as control) at 202 μM in RhoP23H/+ retinal explants and 64 μM in WT retinae [2].
YC-001(50 or 200 mg kg-1, i.p. )protects Abca4-/-Rdh8-/- mice from bright light-induced retinal degeneration [1].About 70 pmol per eye of YC-001 was detected at 0.5 h after i.p. injection at 200 mg kg-1 bw, increasing to 280 pmol per eye at 3 h, and then diminishing to an undetectable level by 24 h [1].YC-001 showed fast ocular clearance with a t1/2 at 0.68 hours [2].
References:
[1]:Chen Y, Chen Y, Jastrzebska B, et al. A novel small molecule chaperone of rod opsin and its potential therapy for retinal degeneration[J]. Nature communications, 2018, 9(1): 1-18.
[2]:Vats A, Xi Y, Feng B, et al. Nonretinoid chaperones improve rhodopsin homeostasis in a mouse model of retinitis pigmentosa[J]. JCI insight, 2022, 7(10).
YC-001 是一种非视黄醛化合物，经证实对视杆细胞视蛋白 [1] 具有反向激动剂和拮抗剂活性。 YC-001 的基于细胞的 β-Gal 片段互补活性（EC50:8.7μM）显示出 7.8 μM 的效力和对照活性评分的 150-310% 的功效[1]。< /p>\n
YC-001（0.5、1、5、10、20、40 μM）改善 P23H 视蛋白突变体 [1] 的糖基化特征。 YC-001 (0,-1.5 μM) 可逆地结合杆状视蛋白，EC50 为 0.98 μM [1]。 YC-001（0.313、0.625、1.25、2.5、5、10、20、80 μM）在 NIH3T3 细胞中以剂量依赖性方式增加 cAMP 水平 [1]。 YC-001 将 27 种引起 adRP 的 RHO 突变体中的多种拯救到 NIH3T3 细胞。 9-cis-retinal、F5257-0462 和 YC-001 分别挽救了 16、11 和 7 个突变体的细胞表面转运[2]。
YC-001（40 μM，48 小时）主要通过降低 ONL 中错误折叠的 RhoP23H 突变体的水平来增加纤毛靶向 RHOP23H 的百分比，这是由 RHOP23H 总蛋白负荷降低引起的[2]。 YC-001 提高 RHO 蛋白质量和 RhoP23H/+ 视网膜的蛋白质稳态 [2]。YC-001 显示 TC50（导致细胞生长 50% 的化学物质的毒性浓度，以及对照) 在 RhoP23H/+ 视网膜外植体中为 202 μM，在 WT 视网膜中为 64 μM [2]。
YC-001（50 或 200 mg kg-1，i.p.）保护 Abca4-/-Rdh8-/- 小鼠免受强光诱导的视网膜变性[1]。每只眼睛约 70 pmol在 i.p. 后 0.5 小时检测到 YC-001。以 200 mg kg-1 bw 的剂量注射，在 3 小时时每只眼睛增加到 280 pmol，然后在 24 小时内减少到检测不到的水平[1]。YC-001 显示出快速的眼部清除率，t1 /2 在 0.68 小时 [2]。
YC-001（0.5、1、5、10、20、40 μM）改善 P23H 视蛋白突变体 [1] 的糖基化特征。 YC-001 (0,-1.5 μM) 可逆地结合杆状视蛋白，EC50 为 0.98 μM [1]。 YC-001（0.313、0.625、1.25、2.5、5、10、20、80 μM）在 NIH3T3 细胞中以剂量依赖性方式增加 cAMP 水平 [1]。 YC-001 将 27 种引起 adRP 的 RHO 突变体中的多种拯救到 NIH3T3 细胞。 9-cis-retinal、F5257-0462 和 YC-001 分别挽救了 16、11 和 7 个突变体的细胞表面转运[2]。
YC-001（40 μM，48 小时）主要通过降低 ONL 中错误折叠的 RhoP23H 突变体的水平来增加纤毛靶向 RHOP23H 的百分比，这是由 RHOP23H 总蛋白负荷降低引起的[2]。 YC-001 提高 RHO 蛋白质量和 RhoP23H/+ 视网膜的蛋白质稳态 [2]。YC-001 显示 TC50（导致细胞生长 50% 的化学物质的毒性浓度，以及对照) 在 RhoP23H/+ 视网膜外植体中为 202 μM，在 WT 视网膜中为 64 μM [2]。
YC-001（50 或 200 mg kg-1，i.p.）保护 Abca4-/-Rdh8-/- 小鼠免受强光诱导的视网膜变性[1]。每只眼睛约 70 pmol在 i.p. 后 0.5 小时检测到 YC-001。以 200 mg kg-1 bw 的剂量注射，在 3 小时时每只眼睛增加到 280 pmol，然后在 24 小时内减少到检测不到的水平[1]。YC-001 显示出快速的眼部清除率，t1 /2 在 0.68 小时 [2]。
| Cas No. | 748778-73-6 | SDF | Download SDF |
| 分子式 | C12H7ClO2S2 | 分子量 | 282.77 |
| 溶解度 | DMSO : 100 mg/mL (353.64 mM; Need ultrasonic) | 储存条件 | Store at -20°C |
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1 mg | 5 mg | 10 mg |
| 1 mM | 3.5364 mL | 17.6822 mL | 35.3644 mL |
| 5 mM | 0.7073 mL | 3.5364 mL | 7.0729 mL |
| 10 mM | 0.3536 mL | 1.7682 mL | 3.5364 mL |
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Nonretinoid chaperones improve rhodopsin homeostasis in a mouse model of retinitis pigmentosa
JCI Insight 2022 May 23;7(10):e153717.PMID:35472194DOI:10.1172/jci.insight.153717.
Rhodopsin-associated (RHO-associated) retinitis pigmentosa (RP) is a progressive retinal disease that currently has no cure. RHO protein misfolding leads to disturbed proteostasis and the death of rod photoreceptors, resulting in decreased vision. We previously identified nonretinoid chaperones of RHO, including YC-001 and F5257-0462, by small-molecule high-throughput screening. Here, we profile the chaperone activities of these molecules toward the cell-surface level of 27 RP-causing human RHO mutants in NIH3T3 cells. Furthermore, using retinal explant culture, we show that YC-001 improves retinal proteostasis by supporting RHO homeostasis in RhoP23H/+ mouse retinae, which results in thicker outer nuclear layers (ONL), indicating delayed photoreceptor degeneration. Interestingly, YC-001 ameliorated retinal immune responses and reduced the number of microglia/macrophages in the RhoP23H/+ retinal explants. Similarly, F5257-0462 also protects photoreceptors in RhoP23H/+ retinal explants. In vivo, intravitreal injection of YC-001 or F5257-0462 microparticles in PBS shows that F5257-0462 has a higher efficacy in preserving photoreceptor function and delaying photoreceptor death in RhoP23H/+ mice. Collectively, we provide proof of principle that nonretinoid chaperones are promising drug candidates in treating RHO-associated RP.
A novel small molecule chaperone of rod opsin and its potential therapy for retinal degeneration
Nat Commun 2018 May 17;9(1):1976.PMID:29773803DOI:10.1038/s41467-018-04261-1.
Rhodopsin homeostasis is tightly coupled to rod photoreceptor cell survival and vision. Mutations resulting in the misfolding of rhodopsin can lead to autosomal dominant retinitis pigmentosa (adRP), a progressive retinal degeneration that currently is untreatable. Using a cell-based high-throughput screen (HTS) to identify small molecules that can stabilize the P23H-opsin mutant, which causes most cases of adRP, we identified a novel pharmacological chaperone of rod photoreceptor opsin, YC-001. As a non-retinoid molecule, YC-001 demonstrates micromolar potency and efficacy greater than 9-cis-retinal with lower cytotoxicity. YC-001 binds to bovine rod opsin with an EC50 similar to 9-cis-retinal. The chaperone activity of YC-001 is evidenced by its ability to rescue the transport of multiple rod opsin mutants in mammalian cells. YC-001 is also an inverse agonist that non-competitively antagonizes rod opsin signaling. Significantly, a single dose of YC-001 protects Abca4 -/- Rdh8 -/- mice from bright light-induced retinal degeneration, suggesting its broad therapeutic potential.